This proposal is designed to provide the principal investigator, Daniel P. Judge, with the necessary scientific experience to allow for a successful transition to an independent career as a clinical scientist. Dr. Judge outlines a five-year plan to identify the factors responsible for the cardiovascular manifestations of Marfan syndrome, including aortic aneurysm and cardiac valve dysfunction. This work will be performed under the mentorship of Harry C. Dietz, professor of Pediatrics, Medicine, Molecular Biology, Neurosurgery, and Genetics at Johns Hopkins University. Dr. Dietz has studied Marfan syndrome for the past 15 years, and he was the first to identify that mutations in the gene encoding fibrillin-1 cause this disorder. He has a long record of successful mentorship of graduate students. A consultant, Dr. David Huso, is a highly skilled veterinary pathologist who will work closely with Dr. Judge, training him in the histopathology of aortic and cardiovascular disease in the mouse models. In addition, an advisory committee of expert clinical scientists will provide both scientific and career advice. The candidate received his M.D. in 1993, followed by a three-year internal medicine residency and a four-year post-doctoral fellowship in cardiology. In July 2000, he became an Assistant Professor at Johns Hopkins University. He has spent the past 3.5 years in the laboratory of his mentor, Dr. Dietz, investigating the molecular pathogenesis of Marfan syndrome. The work will focus on the pathogenesis of the cardiovascular manifestations of Marfan syndrome, including aortic aneurysm, aortic dissection, and cardiac valve thickening. Using several novel murine models that the candidate has developed, he will address issues of pathogenesis and therapy for these conditions. Specific aims include: 1) Evaluation of the contribution of dominant-negative interference versus haploinsufficiency for fibrillin-1 in the pathogenesis of MFS, 2) Elucidation of the contribution of dysregulated TGFbeta activity in the cardiovascular pathogenesis of MFS, and 3) Pharmacologic modulation of the pathogenetic sequence of events leading to aneurysm formation. This work has relevance to nonsyndomic aneurysm and cardiac valve insufficiency. Dr. Judge's training will be based in the School of Public Health at Johns Hopkins, and he will be advised by a committee of experts to create a fruitful environment for the development of an independent clinical scientist.